Improving Autophagy In Cystic Fibrosis

Cystic Fibrosis (CF) is a fatal, genetic disorder that critically affects the lungs and is directly caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR protein function. Autophagy is a highly-regulated biological process that provides energy during periods of stress and starvation. Normally, it functions to clear pathogens and dysfunctional protein aggregates within macrophages. This process is impaired in CF patients and CF mice, as their macrophages exhibit limited autophagy activity. The low expression of autophagy genes, characteristic of CF cells, promoted us to examine transcriptional and translational regulation of autophagy molecules resulting from microRNA (miRNA, miR) and epigenetic variations. The study of microRNAs (miRNAs, miRs) continues to offer novel therapeutic targets. The objective of this study was to elucidate the role miRNAs play in the dysregulation of autophagy in CF macrophages and target them to restore this process and improve CFTR function. We identified the miR-17~92 cluster as a potential negative regulator of autophagy since CF macrophages exhibit increased cluster expression compared to wildtype (WT). The absence of the cluster increased autophagy protein expression, suggesting the canonical inverse relationship between miR-17~92 expression and autophagy gene expression which was further validated by luciferase assays. Downregulation of miR-17 and miR-20a restored autophagy expression in the lungs of CF mice. Notably, down-regulation of these inherently elevated miRNAs in vitro improved CFTR function, the fundamental cause of CF and its symptoms, via restoration of autophagy in macrophages.